Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same

ABSTRACT

A main object of the present invention is to provide a novel crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”). A Form-I crystal of compound A shows diffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees in the powder X-ray diffraction spectrum thereof. A Form-II crystal of compound A shows diffraction peaks at 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees in the powder X-ray diffraction spectrum thereof. A Form-III crystal of compound A shows diffraction peaks at 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees in the powder X-ray diffraction spectrum thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a U.S. national stage application under 35U.S.C. §371 of International Patent Application No. PCT/JP2010/060798filed on Jun. 25, 2010, which claims the benefit of foreign priority toJapanese Patent Application No. UP 2009-151727 filed on Jun. 26, 2009,Japanese Patent Application No. JP 2009-151728 filed on Jun. 26, 2009,and Japanese Patent Application No. JP 2009-151729 filed on Jun. 26,2009, the disclosures of all of which are hereby incorporated byreference in their entireties. The International Application waspublished in Japanese on Dec. 29, 2010, as International Publication No.WO 2010/150865 A1 under PCT Article 21(2).

FIELD OF THE INVENTION

The present invention relates to a crystal of2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide(hereinafter referred to as “compound A”).

BACKGROUND OF THE INVENTION

Compound A has an excellent PGI2 agonistic effect and shows a plateletaggregation inhibitory effect, a vasodilative effect, a bronchodilativeeffect, a lipid deposition inhibitory effect, a leukocyte activationinhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO'084”)).

Specifically, compound A is useful as preventive or therapeutic agentsfor transient ischemic attack (TIA), diabetic neuropathy, diabeticgangrene, peripheral circulatory disturbance (e.g., chronic arterialocclusion, intermittent claudication, peripheral embolism, vibrationsyndrome, Raynaud's disease), connective tissue disease (e.g., systemiclupus erythematosus, scleroderma, mixed connective tissue disease,vasculitic syndrome), reocclusion/restenosis after percutaneoustransluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis(e.g., acute-phase cerebral thrombosis, pulmonary embolism),hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebralinfarction, myocardial infarction), angina (e.g., stable angina,unstable angina), glomerulonephritis, diabetic nephropathy, chronicrenal failure, allergy, bronchial asthma, ulcer, pressure ulcer(bedsore), restenosis after coronary intervention such as atherectomyand stent implantation, thrombocytopenia by dialysis, the diseases inwhich fibrosis of organs or tissues is involved [e.g., Renal diseases(e.g., tuburointerstitial nephritis), respiratory diseases (e.g.,interstitial pneumonia (pulmonary fibrosis), chronic obstructivepulmonary disease), digestive diseases (e.g., hepatocirrhosis, viralhepatitis, chronic pancreatitis and scirrhous stomachic cancer),cardiovascular diseases (e.g, myocardial fibrosis), bone and articulardiseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skindiseases (e.g, cicatrix after operation, scalded cicatrix, keloid, andhypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinarydiseases (e.g., prostatic hypertrophy), other diseases (e.g.,Alzheimer's disease, sclerosing peritonitis; type I diabetes and organadhesion after operation)], erectile dysfunction (e.g., diabeticerectile dysfunction, psychogenic erectile dysfunction, psychoticerectile dysfunction, erectile dysfunction associated with chronic renalfailure, erectile dysfunction after intrapelvic operation for removingprostata, and vascular erectile dysfunction associated with aging andarteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis,Crohn's disease, intestinal tuberculosis, ischemic colitis andintestinal ulcer associated with Behcet disease), gastritis, gastriculcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinalvein occlusion, ischemic optic neuropathy), sudden hearing loss,avascular necrosis of bone, intestinal damage caused by administrationof a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam,oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen,celecoxib) (there is no particular limitation for the intestinal damageso far as it is damage appearing in duodenum, small intestine and largeintestine and examples thereof include mucosal damage such as erosionand ulcer generated in duodenum, small intestine and large intestine),and symptoms associated with lumbar spinal canal stenosis (e.g.,paralysis, dullness in sensory perception, pain, numbness, lowering inwalking ability, etc. associated with cervical spinal canal stenosis,thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffusespinal canal stenosis or sacral stenosis) etc. (see, for example, in WO'084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397,and WO 2009/157398).

In addition, compound A is useful as an accelerating agent for genetherapy or angiogenesis therapy such as autologous bone marrowtransplantation, an accelerating agent for angiogenesis in restorationof peripheral artery or angiogenic therapy, etc. (see, for example, inWO '084).

As mentioned above, while the usefulness of compound A as therapeuticagents for the above-mentioned disorders is known, no referencedescribes or suggests the possibility of existence of crystals ofcompound A.

BRIEF SUMMARY OF THE INVENTION

A main object of the present invention is to provide a novel crystal ofcompound A. Additionally, an object of the present invention is toprovide a method for producing the crystal, and a pharmaceuticalcomposition containing the crystal as an active ingredient.

It is hoped that medicament bulk is a thing of a high quality for whichconstant effect can be always shown and of a form which is handledeasily industrially. The present inventors have earnestly studied. As aresult, the present inventors have found a novel crystal of compound A,and have completed the present invention.

The present invention includes, for example, the following aspects.

One aspect is Form-I crystal of compound A which shows diffraction peaksin the powder X-ray diffraction spectrum of compound A (hereinafterreferred to as “Form-I crystal of the invention”) at the followingangles of diffraction 2θ: 9.4 degrees, 9.8 degrees, 17.2 degrees and19.4 degrees, wherein the X-ray powder diffraction diagram is obtainedby using Cu Kα radiation (λ=1.54 Å),

Another aspect is Form-II crystal of compound A which shows diffractionpeaks in the powder X-ray diffraction spectrum of compound A(hereinafter referred to as “Form-II crystal of the invention”) at thefollowing angles of diffraction 2θ: 9.0 degrees, 12.9 degrees, 20.7degrees and 22.6 degrees, wherein the X-ray powder diffraction diagramis obtained by using Cu Kα radiation (λ=1.54 Å),

Another aspect of the present invention is Form-III crystal of compoundA which shows diffraction peaks in the powder X-ray diffraction spectrumof compound A (hereinafter referred to as “Form-III crystal of theinvention”) at the following angles of diffraction 2θ: 9.3 degrees, 9.7degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees, wherein the X-raypowder diffraction diagram is obtained by using Cu Kα radiation (λ=1.54Å)

Yet another aspect of the present invention is a pharmaceuticalcomposition containing the crystal of one of the above three as theactive ingredient (hereinafter referred to as “pharmaceuticalcomposition of the invention”).

When specifying an angle of diffraction 2 theta (2θ) for a peak in theinvention embodiments and the claims, it should be understood that thevalue given is to be understood as an interval from said value minus0.2° to said value plus 0.2°, and preferably from said value minus 0.1°to said value plus 0.1°.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction spectrum chart of Form-I crystalof the invention. The vertical axis indicates the peak intensity (cps),and the horizontal axis indicates the diffraction angle (2θ[°]).

FIG. 2 shows a powder X-ray diffraction spectrum chart of Form-IIcrystal of the invention. The vertical axis indicates the peak intensity(cps), and the horizontal axis indicates the diffraction angle (2θ[°]).

FIG. 3 shows a powder X-ray diffraction spectrum chart of Form-IIIcrystal of the invention. The vertical axis indicates the peak intensity(cps), and the horizontal axis indicates the diffraction angle (2θ[°]).

FIG. 4 shows a scanning electron micrograph of Form-I crystal of theinvention.

FIG. 5 shows a scanning electron micrograph of Form-II crystal of theinvention.

FIG. 6 shows a scanning electron micrograph of Form-III crystal of theinvention.

DETAILED DESCRIPTION OF TEE INVENTION

Form-I crystal of the invention is characterized in that it showsdiffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4degrees in the powder X-ray diffraction spectrum of compound A.

Form-II crystal of the invention is characterized in that it showsdiffraction peaks at 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6degrees in the powder X-ray diffraction spectrum of compound A.

Form-III crystal of the invention is characterized in that it showsdiffraction peaks at 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6degrees and 23.5 degrees in the powder X-ray diffraction spectrum ofcompound A.

A. Production of Compound A

Compound A can be produced, for example, according to the methoddescribed in WO '084, and, it can also be produced according to theproduction method mentioned below.

Step 1:

6-Iodo-2,3-diphenylpyrazine can be produced from6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. Thereaction is carried out in the presence of an acid in an organic solvent(e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, ortheir mixed solvent). The acid to be used is, for example, acetic acid,sulfuric acid, or their mixed acid. The amount of sodium iodide to beused is generally within a range of from 1 to 10 molar ratio relative to6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3molar ratio. The reaction temperature varies depending on the kinds ofthe solvent and the acid to be used, but may be generally within a rangeof from 60° C. to 90° C. The reaction time varies depending on the kindsof the solvent and the acid to be used and on the reaction temperature,but may be generally within a range of from 9 hours to 15 hours.

Step 2:

5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be producedfrom 6-iodo-2,3-diphenylpyrazine by reacting it with4-hydroxybutyl(isopropyl)amine. The reaction is carried out in thepresence of a base in an organic solvent (e.g., sulfolane,N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide ortheir mixed solvent). The base to be used is, for example, sodiumhydrogencarbonate, potassium hydrogencarbonate, potassium carbonate,sodium carbonate or their mixed base. The amount of4-hydroxybutyl(isopropyl)amine to be used may be generally within arange of from 1.5 to 5.0 molar ratio relative to6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3molar ratio. The reaction temperature varies depending on the kinds ofthe solvent and the base to be used, but may be generally within a rangeof from 170° C. to 200° C. The reaction time varies depending on thekinds of the solvent and the base to be used and on the reactiontemperature, but may be generally within a range of from 5 hours to 9hours.

Step 3:

Compound A can be produced from5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting itwith N-(2-chloroacetyl)methanesulfonamide. The reaction is carried outin the presence of a base in a solvent (N-methylpyrrolidone,2-methyl-2-propanol or their mixed solvent). The base to be used is, forexample, potassium t-butoxide, sodium t-butoxide or their mixed base.The amount of N-(2-chloroacetyl)methanesulfonamide to be used may begenerally within a range of from 2 to 4 molar ratio relative to5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferablywithin a range of from 2 to 3 molar ratio. The reaction temperaturevaries depending on the kinds of the solvent and the base to be used,but may be generally within a range of from −20° C. to 20° C. Thereaction time varies depending on the kinds of the solvent and the baseto be used and on the reaction temperature, but may be generally withina range of from 0.5 hours to 2 hours.

The compounds to be used as the starting materials in theabove-mentioned production method for compound A are known compounds, orcan be produced by known methods.

B. Productions of Form-I Crystal of the Invention, Form-II Crystal ofthe Invention, and Form-III Crystal of the Invention (HereinafterCollectively Referred to as “the Crystals of the Invention”)

(I) Production of Form-I Crystal of the Invention

Form-I crystal of the invention can be produced, for example, accordingto the method described below.

(1) Dissolution Step

This step is a step of dissolving compound A in a solvent by heating.The suitable solvent to be used in the step is, for example, alcoholicsolvent, a mixed solvent of alcoholic solvent and ketone solvent. Thesuitable alcoholic solvent to be used in the step is, for example,methanol, ethanol, 2-propanol, preferably ethanol. The suitable ketonesolvent to be used in the step is, for example, methylethylketone.

Especially, the preferable solvent to be used in the step is ethanol ora mixed solvent of ethanol and methylethylketone. In case of a mixedsolvent of ethanol and methylethylketone, ethanol is within a range offrom 1.5-fold (V/v) to 100-fold (v/v) relative to the amount ofmethylethylketone, preferably within a range of from 3-fold (v/v) to50-fold (v/v), more preferably within a range of from 6-fold (v/v) to20-fold (v/v).

The total volume of the solvent to be used in the step is preferablywithin a range of from 2-fold (mL/g) to 30-fold (mL/g) relative to theamount of compound A, more preferably within a range of from 3-fold(mL/g) to 20-fold (mL/g), further more preferably within a range of from4-fold (mL/g) to 15-fold (mL/g). The heating temperature variesdepending on the kind of solvent and the volume of the solvent used, butgenerally is lower than the boiling point of the solvent to be used, andis preferably within a range of from 60° C. to 100° C., more preferablywithin a range of from 70° C. to 90° C.

In the step, the solution may be filtered to remove insolubles, ifnecessary. To prevent the precipitation of crystals during thefiltration, the filtration is preferably carried out under pressureusing a funnel equipped with a heating device. In case the precipitationof crystals is observed in the filtrate, the precipitate is preferablydissolved again by reheating after the filtration.

(2) Cooling Step

This step is a step of precipitating Form-I crystal of the inventionfrom the solution prepared in the above step (1) by cooling. The step ispreferably carried out by using a crystallizer equipped with a heatingfunction and a stirring function.

The cooling temperature (temperature when precipitated crystal iscollected) is, suitably, within a range of from −10° C. to 50° C.,preferably within a range of from 0° C. to 20° C., and more preferablywithin a range of from 0° C. to 10° C. The step is preferably carriedout by cooling within a range of from 3 hours to 95 hours slowly untilreaching the cooling temperature.

Additionally, in the step, a seed of Form-I crystal of the invention maybe added. In that case, it is preferable that the seed of Form-I crystalof the invention is added when the solution is cooled to a temperaturewithin a range of from 60° C. to 90° C. The amount of the seed crystalof Form-I crystal of the invention is preferably within a range of from1% to 10% by weight relative to the amount of compound A.

(3) Crystal Collection and Drying Step

This step is a step of collecting the precipitated crystal obtained inthe above step (2) using a known means such as filtration andcentrifugation, and drying the collected crystal.

A drying step can be carried out by a conventional method such as dryingunder reduced pressure and over a desiccant. Drying is preferablycarried out under reduced pressure (e.g., 10 mmHg or less) at within arange of from 20° C. to 70° C. for one hour to 48 hours.

Additionally, following the above step (1), after partiallyprecipitating crystal by removing the solvent while heating and stirringthe solution prepared in the above step (1), Form-I crystal of theinvention can be obtained by carrying out the above steps (2) and (3).In the step of removing the solvent, the seed of Form-I crystal of theinvention may be added. The amount of the seed of Form-I crystal of theinvention is preferably within a range of from 0.1% to 10% by weightrelative to the amount of compound A used in the above step (1).

(II) Production of Form-II Crystal of the Invention

Form-II crystal of the invention can be produced, for example, accordingto the method described below.

(1) Dissolution Step

This step is a step of dissolving compound A in a solvent by heating.The suitable solvent to be used in the step is, for example, alcoholicsolvent, ketone solvent, a saturated hydrocarbon solvent, ether solvent,and water, or a mixed solvent thereof. The preferable mixed solvent is amixture of ether solvent and a saturated hydrocarbon solvent or water,or a mixture of alcohol solvent and ketone solvent or water.

The alcoholic solvent to be used in the step is, for example, a straightor branched alcohol having one to 8 carbon atoms. Specifically, thealcohol solvent may include methanol, ethanol, n-propanol, isopropanol,1-butanol, 2-butanol, t-butanol, 1-amylalcohol, 1-hexanol, 1-heptanol,1-octanol. The ether solvent to be used in the step may includetetrahydrofuran, 1,4-dioxane. The saturated hydrocarbon solvent to beused in the step is, for example, a straight or branched alkane having 6to 8 carbon atoms, or a cycloalkane having 6 to 8 carbon atoms.Specifically, the saturated hydrocarbon solvent may include heptane,octane, cyclohexane, cycloheptane, cyclooctane. The ketone solvent to beused in the step is, for example, a straight or branched one having 3 to8 carbon atoms. Specifically, the ketone solvent may include acetone,methylethylketone.

The total volume of the solvent to be used in the step is suitablywithin a range of from 2-fold (mL/g) to 20-fold (mL/g) relative to theamount of compound A, preferably within a range of from 3-fold (mL/g) to15-fold (mL/g), more preferably within a range of from 5-fold (mL/g) to10-fold (mL/g). The heating temperature varies depending on the kind ofsolvent and the volume of the solvent used, but generally is lower thanthe boiling point of the solvent to be used, and is preferably within arange of from 60° C. to 90° C., more preferably within a range of from70° C. to 80° C.

In the step, the solution may be filtered to remove insolubles, ifnecessary. To prevent the precipitation of crystals during thefiltration, the filtration is preferably carried out under pressureusing a funnel equipped with a heating device. In case the precipitationof crystals is observed in the filtrate, the precipitate is preferablydissolved again by reheating after the filtration.

(2) Cooling Step

This step is a step of precipitating Form-II crystal of the inventionfrom the solution prepared in the above step (1) by cooling. The step ispreferably carried out by using a crystallizer equipped with a heatingfunction and a stirring function.

The cooling temperature (temperature when precipitated crystal iscollected) is suitably within a range of from −10° C. to 50° C.,preferably within a range of from 0° C. to 20° C., and more preferablywithin a range of from 0° C. to 10° C.

Additionally, in the step, a seed of Form-II crystal of the inventionmay be added. The amount of the seed of Form-II crystal of the inventionis preferably within a range of from 1% to 10% by weight relative to theamount of compound A.

In case Form-II crystal of the invention is produced by using alcoholicsolvent or a mixture of alcoholic solvent and ketone solvent as asolvent, it is necessary that the seed of Form-II crystal of theinvention be added in the solution prepared in the above step (1) andthe solution be cooled, or the solution prepared in the above step (1)be cooled rapidly. The cooling rate is suitably within a range of from60° C./hour to 600° C./hour.

(3) Crystal Collection and Drying Step

This step is the same as the method described above in “(3) Crystalcollection and drying step” in the above-mentioned “(I) Production ofForm-I Crystal of the Invention.”

(III) Production of Form-III Crystal of the Invention

Form-III crystal of the invention can be produced, for example,according to the method described below.

(1) Dissolution Step

This step is a step of dissolving compound A in a solvent by heating.The suitable solvent to be used in the step is, for example, estersolvent, aromatic hydrocarbon solvent. The suitable ester solvent to beused in the step is, for example, diethylcarbonate, n-butyl acetate,isoamyl acetate, n-amyl acetate, preferably n-butyl acetate. Thesuitable aromatic hydrocarbon solvent to be used in the step is, forexample, ethylbenzene.

The total volume of the solvent to be used in the step is suitablywithin a range of from 5-fold (mL/g) to 30-fold (mL/g) relative to theamount of compound A, preferably within a range of from 7-fold (mL/g) to20-fold (mL/g), more preferably within a range of from 10-fold (mL/g) to15-fold (mL/g). The heating temperature varies depending on the kind ofsolvent and the volume of the solvent used, but generally is lower thanthe boiling point of the solvent to be used, preferably within a rangeof from 40° C. to 90° C., and more preferably within a range of from 50°C. to 80° C.

In the step, the solution may be filtered to remove insolubles, ifnecessary. To prevent the precipitation of crystals during thefiltration, the filtration is preferably carried out under pressureusing a funnel equipped with a heating device. In case the precipitationof crystals is observed in the filtrate, the precipitate is preferablydissolved again by reheating after the filtration.

(2) Cooling Step

This step is a step of precipitating Form-III crystal of the inventionfrom the solution prepared in the above step (1) by cooling. The step ispreferably carried out using a crystallizer equipped with a heatingfunction and a stirring function.

The cooling rate is suitably within a range of from 0.5° C./hour to 120°C./hour. The cooling temperature (temperature when precipitated crystalis collected) is suitably within a range of from −10° C. to 30° C.,preferably within a range of from 0° C. to 20° C., and more preferablywithin a range of from 0° C. to 10° C.

(3) Crystal Collection and Drying Step

The step is the same as the method described above in “(3) Crystalcollection and drying step” in the above-mentioned “(I) Production ofForm-I Crystal of the Invention.”

C. Medical Use and Pharmaceutical Composition of the Invention

Compound A according to the present invention has an excellent PGI2agonistic effect and shows a platelet aggregation inhibitory effect, avasodilative effect, a bronchodilative effect, a lipid depositioninhibitory effect, a leukocyte activation inhibitory effect, etc.

Therefore, the crystals of the invention or the pharmaceuticalcomposition of the invention is useful as preventive or therapeuticagents for transient ischemic attack (TIA), diabetic neuropathy,diabetic gangrene, peripheral circulatory disturbance (e.g., chronicarterial occlusion, intermittent claudication, peripheral embolism,vibration syndrome, Raynaud's disease), connective tissue disease (e.g.,systemic lupus erythematosus, scleroderma, mixed connective tissuedisease, vasculitic syndrome), reocclusion/restenosis after percutaneoustransluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis(e.g., acute-phase cerebral thrombosis, pulmonary embolism),hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebralinfarction, myocardial infarction), angina (e.g., stable angina,unstable angina), glomerulonephritis, diabetic nephropathy, chronicrenal failure, allergy, bronchial asthma, ulcer, pressure ulcer(bedsore), restenosis after coronary intervention such as atherectomyand stent implantation, thrombocytopenia by dialysis, the diseases inwhich fibrosis of organs or tissues is involved [e.g., renal diseases(e.g., tuburointerstitial nephritis), respiratory diseases (e.g.,interstitial pneumonia (pulmonary fibrosis), chronic obstructivepulmonary disease), digestive diseases (e.g., hepatocirrhosis, viralhepatitis, chronic pancreatitis and scirrhous stomachic cancer),cardiovascular diseases (e.g, myocardial fibrosis), bone and articulardiseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skindiseases (e.g, cicatrix after operation, scalded cicatrix, keloid, andhypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinarydiseases (e.g., prostatic hypertrophy), other diseases (e.g.,Alzheimer's disease, sclerosing peritonitis, type I diabetes and organadhesion after operation)], erectile dysfunction (e.g., diabeticerectile dysfunction, psychogenic erectile dysfunction, psychoticerectile dysfunction, erectile dysfunction associated with chronic renalfailure, erectile dysfunction after intrapelvic operation for removingprostata, and vascular erectile dysfunction associated with aging andarteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis,Crohn's disease, intestinal tuberculosis, ischemic colitis andintestinal ulcer associated with Behcet disease), gastritis, gastriculcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinalvein occlusion, ischemic optic neuropathy), sudden hearing loss,avascular necrosis of bone, intestinal damage caused by administrationof a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam,oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen,celecoxib) (there is no particular limitation for the intestinal damageso far as it is damage appearing in duodenum, small intestine and largeintestine and examples thereof include mucosal damage such as erosionand ulcer generated in duodenum, small intestine and large intestine),and symptoms associated with lumbar spinal canal stenosis (e.g.,paralysis, dullness in sensory perception, pain, numbness, lowering inwalking ability, etc. associated with cervical spinal canal stenosis,thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffusespinal canal stenosis or sacral stenosis) etc. In addition, the crystalsof the invention or the pharmaceutical composition of the invention isalso useful as an accelerating agent for gene therapy or angiogenesistherapy such as autologous bone marrow transplantation, an acceleratingagent for angiogenesis in restoration of peripheral artery or angiogenictherapy, etc. If the crystals of the invention are administered as amedicine, the pharmaceutical composition of the invention is thecrystals of the invention as it is or contains the crystals of theinvention in a pharmaceutically acceptable, nontoxic and inert carrierwithin a range of from 0.1% to 99.5%, preferably within a range of from0.5% to 90%.

Examples of the carrier include solid, semi-solid or liquid diluent,filler and other auxiliary agents for pharmaceutical formulation. Thesecan be used alone or as a mixture of two or more thereof.

The pharmaceutical composition of the invention may be in any of theforms of oral preparations such as powder, capsules, tablets,sugar-coated tablets, granules, diluted powder, suspension, liquid,syrup, elixir or troche, and parenteral preparations such as injectionor suppository in a solid or liquid dose unit. It may also be in a formof a sustained release preparation. Among them, oral preparations suchas tablets are particularly preferred.

Powder is able to be manufactured by making the crystals of theinvention into an appropriate fine size.

Diluted powder is able to be manufactured by such a manner that thecrystals of the invention are made into an appropriate fine size andthen mixed with a pharmaceutical carrier which is similarly made into afine size such as edible carbohydrate (e.g., starch and mannitol).Flavoring agent, preservative, dispersing agent, coloring agent,perfume, etc. may be optionally added thereto.

Capsules are able to be manufactured by such a manner that the powder ordiluted powder which is made powdery as mentioned above or granuleswhich will be mentioned under the item for tablets are filled in ancapsule shell such as gelatin capsule. It is also possible tomanufacture in such a manner that the powder or the diluted powder in apowdery form is mixed with a lubricant or a fluidizing agent such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol followed by subjecting it to a filling operation.When a disintegrating agent or solubilizing agent such as carboxymethylcellulose, carboxymethyl cellulose calcium, lowly-substitutedhydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starchsodium, calcium carbonate or sodium carbonate is added, efficacy of thepharmaceutical when the capsules are ingested can be improved. It isalso possible that fine powder of the crystals of the invention issuspended/dispersed in vegetable oil, polyethylene glycol, glycerol orsurfactant and wrapped with a gelatin sheet to give a soft capsulepreparation.

Tablets are able to be manufactured in such a manner that a powderymixture is prepared by addition of a filler to the crystals of theinvention which have been made powdery and made into granules or slugsand then a disintegrating agent or a lubricant is added thereto followedby making them into tablets.

The powdery mixture is able to be manufactured by mixing appropriatelypowdered crystals of the invention with a diluent or a base. Ifnecessary, it is possible to add a binder (such as carboxymethylcellulose sodium, methyl cellulose, hydroxypropyl methyl cellulose,gelatin, polyvinylpyrrolidone or polyvinyl alcohol), a dissolutionretarding agent (such as paraffin), a reabsorbing agent (such as aquaternary salt), an adsorbent (such as bentonite or kaolin), etc.thereto.

The powdery mixture is able to be made into granules in such a mannerthat it is firstly made wet by using a binder, for example, syrup,starch paste, acacia, cellulose solution or polymer solution, mixed withstirring and dried followed by grinding. Instead of making the powderinto granules as such, it is also possible that the powder is applied toa tabletting machine and the resulting slug in an incomplete shape isground to give granules. When a lubricant such as stearic acid,stearate, talc or mineral oil is added to the granules prepared as such,sticking of the granules to each other can be prevented.

Tablets are also able to be manufactured in such a manner that thecrystals of the invention are mixed with a fluid inert carrier and thendirectly making them into tablets without conducting the above steps ofmaking them into granules or slugs.

The tablets prepared as such can be subjected to film coating or sugarcoating. It is also possible to apply a transparent or semi-transparentprotective coat made of a tightly closed shellac film, a coat made ofsugar or polymer material, or a polished coat made of wax.

In other oral preparations such as liquid, syrup, troche or elixir, itis also possible to make it into a dose unit form wherein apredetermined amount thereof contains a predetermined amount of thecrystal of the present invention.

The syrup is able to be manufactured by dissolving the crystals of theinvention into an appropriate aqueous solution of a flavor. The elixiris able to be manufactured by using a non-toxic alcoholic carrier.

The suspension is able to be manufactured by dispersing the crystals ofthe invention into a non-toxic carrier. If necessary, it is possible toadd a solubilizing agent or an emulsifier (such as ethoxylatedisostearyl alcohol and polyoxyethylene sorbitol ester), a preservativeor a flavor-endowing agent (such as peppermint oil or saccharine)thereto.

If necessary, the dose unit formulation for oral administration may bemade into microcapsules. The formulation is also able to be coated orembedded into polymer or wax to obtain a prolonged action or sustainedrelease of the active ingredient.

The parenteral preparation may be in a liquid dose unit form forsubcutaneous, intramuscular or intravenous injection such as in a formof solution or suspension. The parenteral preparation is able to bemanufactured in such a manner that a predetermined amount of thecrystals of the invention is suspended or dissolved in a non-toxicliquid carrier meeting the purpose of injection such as aqueous or oilymedium and then the suspension or solution is sterilized. Non-toxic saltor a solution thereof may be added thereto for making the injectionsolution isotonic. It is also possible to add a stabilizer, apreservative, an emulsifier and the like.

The suppository is able to be manufactured by dissolving or suspendingthe crystals of the invention in a low-melting and water-soluble orinsoluble solid such as polyethylene glycol, cacao fat, semi-syntheticfat/oil (such as Witepsol (registered trade mark)), higher ester (suchas myristyl palmitate ester) or a mixture thereof.

Although the dose may vary depending upon the state of a patient such asbody weight or age, administering route or degree of symptom, a range offrom 0.001 mg to 100 mg per day as an amount of the crystals of theinvention is generally suitable for an adult and a range of from 0.01 mgto 10 mg is more preferable. In some cases, a dose less than the abovemay be sufficient or, on the other hand, a dose more than the above maybe necessary. It is also possible to administer one to several times aday or to administer with an interval of one to several days.

EXAMPLES

The present invention is described in more detail with reference toExamples and Test Examples given below; however, the present inventionshould not be limited whatsoever to these Examples.

For the powder X-ray diffractometry, Rigaku Corporation's RINT-UltimaIII (target: Cu, voltage: 40 kV, current: 40 mA, scan speed: 4degrees/min) was used.

Example 1 Production of Form-I Crystal of the Invention

Ethanol (440 ml) was added to compound A (40 g), and the mixture wasstirred and heated in an oil bath of 100° C. to 110° C. After compound Awas dissolved, ethanol (280 ml) was removed. The obtained concentratewas stirred and heated under reflux in a water bath of 80° C. for 1hour. The solution was gradually cooled to 10° C. in 20 hours whilestirring, and the precipitated crystal was collected through filtration.The obtained crystal was washed with a small amount of ethanol (48 ml),and dried under reduced pressure at 60° C. to give Form-I crystal of theinvention (38.93 g, 97.3%). A powder X-ray diffraction spectrum of theForm-I crystal of the invention is shown in FIG. 1.

Mp: 140.4° C. (the Japanese Pharmacopoeia, method 1 of Melting PointDetermination)

Example 2 Production of Form-I Crystal of the Invention

Ethanol (99 g) and methylethylketone (11 g) were added to compound A (20g), and heated at 77° C. to dissolve compound A, and then the solutionwas gradually cooled to 10° C. in 20 hours. During cooling, to thesolution was added a small amount of Form-I crystal of the invention.After cooling, the precipitated crystal was collected throughfiltration, washed with ethanol, and dried under reduced pressure togive Form-I crystal of the invention (18.72 g, 93.6%).

Example 3 Production of Form-II Crystal of the Invention

Ethanol (550 g) and methyl ethyl ketone (55 g) were added to compound A(100 g), heated at 77° C., and filtered under pressure while keptheated. With stirring, the resulting filtrate was cooled from 70° C. to0° C., taking 30 minutes, and after reaching 0° C., this was stirred at0° C. for 2.5 hours. The precipitated crystal was collected throughfiltration, washed with ethanol (200 ml), and dried under reducedpressure. Ethanol (99 g) and methyl ethyl ketone (11 g) were added tothe obtained crystal (20 g), heated at 70° C., then kept at 70° C. for 1hour, and gradually cooled to 10° C., taking 20 hours; and afterreaching 10° C., this was stirred at 10° C. for 1 hour. The precipitatedcrystal was collected through filtration, washed with ethanol (40 ml),and dried under reduced pressure to give Form-II crystal of theinvention (18.73 g, 93.7%). A powder X-ray diffraction spectrum ofForm-II crystal of the invention is shown in FIG. 2.

Mp: 135.2° C. (the Japanese Pharmacopoeia, method 1 of Melting PointDetermination)

Example 4 Production of Form-II Crystal of the Invention

Ethanol (99 g) and methylethylketone (11 g) were added to compound A (20g), and heated at 77° C. to dissolve compound A, and then the solutionwas gradually cooled to 10° C. in 20 hours. During cooling, to thesolution was added a small amount of Form-II crystal of the invention.After cooling, the precipitated crystal was collected throughfiltration, washed with ethanol, and dried under reduced pressure togive Form-II crystal of the invention (19.70 g, 98.5%).

Example 5 Production of Form-III Crystal of the Invention

N-Butyl acetate (500 ml) was added to compound A (36.7 g), and heated at75° C. to dissolve compound A, and then cooled to 5° C. Then, a processof heating to 60° C. and cooling to 5° C. was carried out, and theprocess was repeated. The precipitated crystal was collected throughfiltration, washed with a small amount of isopropyl acetate (50 ml), anddried under reduced pressure to give Form-III crystal of the invention(29.0 g, 79.0%). A powder X-ray diffraction spectrum of Form-III crystalof the invention is shown in FIG. 3.

Mp: 138.0° C. (the Japanese Pharmacopoeia, method 1 of Melting PointDetermination)

The crystals of the invention used in the following Test Examples 1 to 3were prepared by the following method.

Form-I crystal of the invention, Form-II crystal of the invention, andForm-III crystal of the invention were prepared in the same methods asin Example 2, Example 4, and Example 5, respectively.

Test Example 1 Measurement of Particle Size

(1) Measurement of Particle Size Distribution of the Crystals of theInvention

After a dispersant (10 mL) was added to the crystals of the invention(20 mg) followed by shaking up, the crystals of the invention weredispersed with ultrasonic wave. The particle size distributions of thecrystals of the invention were measured by using HORIBA LA-910. Theresult is shown in Table 1.

The dispersant used is a filtered saturated solution of compound A in0.1 v/v % Polysorbate 80 aqueous solution.

TABLE 1 Crystal Form D10 D50 D90 1 Form-I Crystal of the Invention 5.612.8 25.8 2 Form-II Crystal of the Invention 5.2 11.3 22.0 3 Form-IIICrystal of the 4.3 8.0 14.4 Invention D10: Cumulative undersize particlediameter at 10% of volumetric ratio [μm] D50: Cumulative undersizeparticle diameter at 50% of volumetric ratio [μm] D90: Cumulativeundersize particle diameter at 90% of volumetric ratio [μm](2) Observation of the Crystals of the Invention with Electron ScanningMicroscope

The crystals were observed through an electron scanning microscope(HITACHI HIGH TECHNOLOGIES TM-1000 Miniscope).

FIG. 4 shows the electron scanning micrograph of Form-I crystal of theinvention. FIG. 5 shows that of Form-II crystal and FIG. 6 shows that ofForm-III crystal.

From the results of (1) end (2) mentioned above, it was concluded thatthe particle size of Form-I crystal of the invention is larger thanthose of Form-II and Form-III crystals.

Test Example 2 Measurement of Residual Solvent Contained in Crystals ofthe Invention

The concentration of residual solvent contained in the crystals of theinvention was measured by using the following measurement conditions.The result is shown in Table 2.

(Measurement Conditions)

GC Apparatus

-   -   Detector: Flame Ionization Detector    -   Column: Capillary Column    -   Column Temperature: 150° C.-230° C.    -   Injection Temperature: 200° C.    -   Detector Temperature: 300° C.    -   Carrier Gas: Helium

TABLE 2 Content Crystal Form Solvent (ppm) 1 Form-I Crystal of theInvention Ethanol 371 Methyl-ethyl-ketone 82 2 Form-II Crystal of theInvention Ethanol 2169 Methyl-ethyl-ketone 246 3 Form-III Crystal of theInvention Isopropyl acetate 93 n-Butyl acetate 2781

Although each crystal Form did not contain a considerable amount ofresidual solvents, the amount of the residual solvents in Form-I crystalof the invention was less than those of Form-II and Form-III.

Test Example 3 Impurity-Removing Effect in Recrystallization

The effectiveness of removing impurities in the course of therecrystallization of each crystal form was measured by using thefollowing measurement conditions (reversed-phase liquid chromatography).

(Measurement Conditions)

HPLC Apparatus

-   -   Detector: Ultraviolet Absorption Detector    -   Column: ODS Column    -   Column Temperature: 40° C.    -   Mobile Phase Mixture of Water, Acetonitrile and Methanesulfonic        acid

The purity (%) of each crystal of compound A was calculated by thefollowing equation.Purity (%)=(Peak area of compound A)/(Total area)×100

The removal ratio of impurities (%) for each crystal was calculated bythe following equation.Removal ratio of impurities (%)={[(Purity of each crystal of compoundA)−(Purity of crude compound A)]/[100−(Purity of crude compound A)]}×100

The result is shown in Table 3.

TABLE 3 Purity of Ratio of Impurity Compound A Removal Crystal Form (%)(%) Crude Material 98.04 1 Form-I Crystal of the Invention 99.51 75 2Form-II Crystal of the Invention 99.33 66 3 Form-III Crystal of theInvention 98.97 47

From the result shown in Table 3, the effectiveness of removingimpurities for Form-I crystal of the invention was the highest comparedwith those for Form-II and III crystals.

Test Example 4 Investigation of Solvent for Crystallization of CompoundA

Investigations of crystallization of compound A were executed accordingto the methods of the following (1) and (2).

(1) Crystallization solvent (see Tables 4 and 5) was added to compoundA, and the mixture was stirred at 50° C. for 60 minutes. The resultingmixture was filtered. After the filtration, the isolated mother liquorwas stirred at 60° C. for 30 minutes, and cooled down to 5° C. over 11hours. After stirring at 5° C. for 72 hours, the precipitated solid wascollected by filtration. The solid was dried at 20° C. under reducedpressure, whereby a solid was obtained.

Powder X-ray diffraction spectrums of the obtained crystals weremeasured and the form of each crystal was determined.

The results are shown in Table 4 (investigation by single solvents) andTable 5 (investigation by mixed solvents).

In the investigation by mixed solvents (Table 5), each solvent was mixedand used in an equal amount.

TABLE 4 Crystallization Solvent Crystal Form 1 tert-Butyl methyl etherNA 2 Acetone Form-II Crystal of the Invention + Form-III Crystal of theInvention 3 Chloroform NA 4 Methanol Form-II Crystal of the Invention +Form-III Crystal of the Invention 5 Tetrahydrofuran Form-II Crystal ofthe Invention + Form-III Crystal of the Invention 6 Isopropyl ether NA 72-Methyltetrahydrofuran Form-II Crystal of the Invention + Form-IIICrystal of the Invention 8 Ethanol NA 9 Cyclohexane NA 10 AcetonitrileForm-II Crystal of the Invention + Form-III Crystal of the Invention 111,2-Dichloroethane NA 12 Fluorobenzene Form-II Crystal of theInvention + Form-III Crystal of the Invention 13 1,2-DimethoxyethaneForm-II Crystal of the Invention + Form-III Crystal of the Invention 14Methylcyclohexane NA 15 Nitromethane Form-II Crystal of the Invention +Form-III Crystal of the Invention 16 1,4-Dioxane NA 173,3-Dimethyl-2-butanone Form-II Crystal of the Invention + Form-IIICrystal of the Invention 18 Isobutanol NA 19 Toluene Form-II Crystal ofthe Invention + Form-III Crystal of the Invention 20 DiethylcarbonateForm-III Crystal of the Invention 21 n-Butyl acetate Form-III Crystal ofthe Invention 22 Chlorobenzene Form-II Crystal of the Invention +Form-III Crystal of the Invention 23 Ethylbenzene NA 24 p-Xylene NA 25Isoamyl acetate Form-III Crystal of the Invention 26 n-Amyl acetateForm-III Crystal of the Invention 27 Methyl-phenyl-ether Form-II Crystalof the invention + Form-III Crystal of the invention 28 Cyclohexanone NA29 bis(2-Methoxy ethyl)ether Form-III Crystal of the invention 301,3,5-Trimethylbenzene Amorphous 31 4-Hydroxy-4-methyl-2- Form-IICrystal of the invention + pentanone Form-III Crystal of the invention32 2,6-Dimethyl-4-heptanone Form-III Crystal of the invention NA: Solidwas not precipitated.

TABLE 5 Crystallization Solvent Crystal Form 1 Chloroform NAAcetonitrile 2 Tetrahydrofuran Form-II Crystal of the InventionCyclohexane 3 Ethyl formate Form-II Crystal of the Invention + WaterForm-III Crystal of the invention 4 Methanol NA Water 5 AcetonitrileForm-II Crystal of the Invention + Water Form-III Crystal of theInvention 6 1,2-Dimethoxyethane Form-II Crystal of the Invention + WaterForm-III Crystal of the Invention 7 Ethanol Form-II Crystal of theInvention Water 8 Cyclohexane Form-II Crystal of the Invention1,4-Dioxane 9 2-Propanol Form-II Crystal of the Invention Water 10Cyclohexanone NA Tetrahydrofuran 11 1-Propanol Form-II Crystal of theInvention Water 12 1,4-Dioxane Form-II Crystal of the Invention Water 132-Butanol Form-II Crystal of the Invention Water 14 CyclohexanoneForm-II Crystal of the Invention + Cyclohexane Form-III Crystal of theInvention 15 1-Butanol Form-II Crystal of the Invention Water 16Cyclohexanone Form-II Crystal of the Invention + 1,4-Dioxane Form-IIICrystal of the Invention NA: Solid was not precipitated.(2) Further investigations were executed using the following method forthose conditions under which crystals were not precipitated (see Tables4 and 5) and conditions similar to them. The solvents used in thefurther experiments were selected in consideration of toxicity,solubility of compound A and availability for industrial use.

An amount of solvent less than that of the test in the above-mentioned(1) was added to compound A, and the mixture was heated to 75° C. withstirring. After dissolving compound A, the mixture was stirred at 65° C.for 5 to 8 hours. The mixture was cooled down to 20° C. over 9 hours.The precipitated crystal was collected by filtration and dried at 70° C.under reduced pressure, whereby a crystal was obtained. The results areshown in Table 6.

In the investigation by mixed solvents, each solvent was mixed and usedin an equal amount.

TABLE 6 Crystallization Solvent Crystal Form 1 tert-Butyl methyl etherNA 2 Isopropyl ether NA 3 Cyclohexane NA 4 Ethanol Form-I Crystal of theInvention 5 2-Propanol Form-I Crystal of the Invention + Form-IIICrystal of the Invention 6 Ethylbenzene Form-III Crystal of theInvention 7 Methanol Form-I Crystal of the Invention + Water Form-IIICrystal of the Invention 8 Cyclohexanone NA Tetrahydrofuran NA: Solidwas not precipitated.

From the results of the above-mentioned (1) and (2), it was concludedthat Form-II crystal of the invention and Form-III crystal of theinvention can be obtained from various solvents.

On the other hand, crystals which contain Form-I crystal of theinvention could be obtained only from alcohol solvents, and highly pureForm-I crystal of the invention could be obtained from ethanol.

The invention claimed is:
 1. A crystal of2-{-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide,showing diffraction peaks in its X-ray powder diffraction spectrum atleast at the following angles of diffraction 2θ: 9.4 degrees, 9.8degrees, 17.2 degrees and 19.4 degrees, wherein the X-ray powderdiffraction diagram is obtained by using Cu Kα radiation.
 2. Apharmaceutical composition comprising the crystal of claim 1 as anactive ingredient.
 3. A method for producing the crystal of claim 1,comprising the steps of dissolving2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamidein an alcoholic solvent or a mixed solvent of an alcoholic solvent and aketone solvent while heating, and subsequently crystallizing2-{-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamideby cooling the solution gradually.